Intra-abdominal pressure to promote hemostasis and survival

ABSTRACT

Systems, methods and kits for treating hemorrhages within cavities are provided. The methods utilize the application of a rapid spike of pressure to the closed cavity, followed by a steady state pressure or pressures.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.14/597,993, filed Jan. 15, 2015, which is a Continuation-in-Part of U.S.patent application Ser. No. 14/455,117, filed Aug. 8, 2014, now U.S.Pat. No. 9,522,215, which claims the benefit of priority to U.S.Provisional Patent Application No. 61/864,368, filed Aug. 9, 2013. U. S.patent application Ser. No. 14/455,117 is also a Continuation-In-Part ofU.S. patent application Ser. No. 13/209,020, filed Aug. 12, 2011, nowU.S. Pat. No. 9,173,817, which is a Continuation-in-Part of U.S. patentapplication Ser. No. 12/862,362, filed Aug. 24, 2010, now abandoned,which claims benefit to U.S. Provisional Patent Application No.61/368,095, filed Jul. 27, 2010 and to U.S. Provisional PatentApplication No. 61/236,314, filed Aug. 24, 2009. The entire disclosureof each of the foregoing references is hereby incorporated by referencefor all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under contract no.W911NF-10-C-0089 awarded by the Defense Advanced Research ProjectsAgency (DARPA). The Government has certain rights in the invention.

TECHNICAL FIELD

Systems and methods relating to polymer foams are generally described.

BACKGROUND

In situ forming polymer foams, such as the Arsenal Foam Technologycommercialized by Arsenal Medical (Watertown, Mass.), have a number ofimportant biomedical applications including the prevention or treatmentof hemorrhage, particularly from noncompressible ordifficult-to-visualize wounds, vascular embolization, arteriovenousmalformation, AV fistulas, abdominal aortic aneurysm, space filling andbulking (e.g. following surgical resection, or for cosmetic purposes),prevention of tissue adhesion, hernia repair, prevention or treatment ofreflux, and temporary or permanent occlusion of body lumens for avariety of applications including sterilization, prevention of calculusmigration during lithotripsy, and other applications. The diversity ofapplications for in situ forming foams reflects significant advantagespossessed by such foams relative to existing technology, including,without limitation their incorporation of well characterized,biocompatible materials; the ability to deliver in situ forming foams toclosed cavities, for example intravascularly; the ability to deliver insitu forming foams to difficult-to-access body sites; the ability of insitu forming foams to expand into empty space, potential space, or intospace filled with blood, support surrounding tissues, and the ability ofthe foam to fill a body cavity.

Foams are typically generated in situ by delivering and mixing multipleliquid-phase components (such as a polyol component and an isocyanatecomponent, which form a polyurethane foam). Pores within the foam may beformed by a blowing reaction and/or by the entrainment of gas before orduring foam formation, and the foam may harden through the formation ofcross-links between prepolymers and/or cross-linking agents. Whendeployed into a body cavity, the liquid components react, driving theexpansion and hardening of the foam. The foam applies pressure to theboundaries of the cavity in a dose dependent and time-dependent manner,for example as shown in the pressure curves of FIG. 1. The shapes ofthese curves are determined by, among other things, the composition andquantity of liquid phase components applied to the body cavity, whichgovern the rates of the blowing and cross-linking reactions and foamproperties (e.g., density or volume expansion, stiffness, pore size,hydrophilicity, absorption capacity).

In situ forming foams are particularly well suited to treatingnoncompressible hemorrhages in challenging settings, including thebattlefield and rural or wilderness settings far from hospital traumacenters. However, in spite of their advantages, in situ forming foamshave not been widely used because of the technical challenges associatedwith developing suitable in situ foaming formulations for differentapplications and delivering of these formulations to body cavities inquantities sufficient to arrest hemorrhages without causing undesirableside effects of excessive pressure such as compartment syndrome.Additionally, to maximize their efficacy in challenging or remotesettings, in situ forming foams should extend patient survival times fora period sufficient to permit evacuation of patients to stations orcenters where hemorrhages can be surgically treated.

SUMMARY OF THE INVENTION

Embodiments of the current invention address the challenges describedabove by providing, in one aspect, a method for treating hemorrhagewithin a body cavity or potential space that includes applying pressureto an interior boundary of the cavity, including pressure to the injuryitself, which pressure is characterized by a transient peak value and byat least one steady state value. In various embodiments, the transientpeak value is between 22 mmHg and about 86 mmHg (e.g. 20, 51 and 84mmHg). The steady state value is, in various embodiments, between about14 mmHg and about 28 mmHg (e.g. 14 or 28 mmHg). Pressure may be applied,in certain embodiments, by an article placed into the closed cavity, andthe article can be a foam which is formed inside of the cavity byapplying a formulation that includes one or more liquid phases into thecavity. In some cases, the steady state pressure occurs within threeminutes and is followed by the steady state value. The steady statevalue may be, in some cases, 30%, 50% or 90% of the transient peakvalue.

In another aspect, the invention relates to a kit for treatinghemorrhage in closed cavities that includes (i) a formulation forforming a foam when disposed into a body, which formulation includes atleast one liquid phase, and (ii) instructions for performing the methodset forth above.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters refer to like featuresthrough the different views. The drawings are not necessarily to scale,with emphasis being placed on illustration of the principles of theinvention.

FIG. 1 plots intra-abdominal pressure over time for four doses of an insitu forming foam in a severe porcine liver hemorrhage model comparedwith an untreated control.

FIG. 2 plots survival curves for porcine treated with four doses of anin situ forming foam in a severe liver hemorrhage model compared with anuntreated control.

FIG. 3 plots the survival times of 81 animals treated either with insitu forming foams or no foam treatment controls against the peakintra-abdominal pressure measured in each animal in a severe liverhemorrhage model.

FIG. 4 plots the survival times of 81 animals treated either with insitu forming foams or no foam treatment control animals against theintra-abdominal pressure measured at 30-minutes post injury in eachanimal in a severe liver hemorrhage model.

FIG. 5 plots intra-abdominal pressure over time for two doses of an insitu forming foam in a severe arterial hemorrhage model.

FIG. 6 plots survival curves for animals treated with two doses of an insitu forming foam in a severe arterial hemorrhage model.

FIG. 7 plots intra-abdominal pressure over time for animals given insitu forming foam, gas insufflation, or no treatment.

FIG. 8 plots intra-abdominal pressure over time in recently deceasedcadaver samples following delivery of an in situ forming foamformulation.

FIG. 9 plots intra-abdominal pressure over time in recently deceasedsubjects (open circles) and swine (closed circles) following delivery ofan in situ forming foam formulation.

FIG. 10 is a bar graph illustrating peak intra-abdominal pressureobserved in recently deceased subjects following delivery of an in situforming foam formulation at varying doses.

FIG. 11 plots change in circumference at the umbilicus over time inrecently deceased subjects following delivery of an in situ forming foamformulation at varying doses.

FIG. 12 is a graphical representation of abdominal organ contact inrecently deceased subjects following delivery of an in situ forming foamformulation at varying doses. Swine data are shown for reference in A;recently deceased study data are shown in B-F.

FIG. 13A is a representative photographic image of foam appearanceduring removal. FIG. 13B is a representative photographic image of foamappearance at a later point during removal. FIG. 13C is a representativephotographic image of foam appearance after removal. FIG. 13D is anotherrepresentative photographic image of foam appearance after removal.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Animal Models

In situ forming polymer foams were deployed at varying dosages in twoanimal models of hemorrhage: First, a lethal grade V hepatic and portalvein injury in swine, as described in Duggan M J, et al. “Development ofa lethal, closed-abdomen grade V hepatoportal injury model innon-coagulopathic swine.” J. Surg. Res. 2013 Jun. 1; 182(1): 101, 107(“Duggan 1”), which is hereby incorporated by reference in its entiretyand for all purposes. In this model, wires were placed strategicallyaround the hepatic vasculature and externalized percutaneously. Afterclosure of a midline incision, the wires were pulled, resulting in asevere, uncontrolled, closed-cavity injury and sudden, massivehypotension. In the absence of intervention the injury was over 90%lethal at one hour.

The second model was a lethal arterial injury, in which a wire wasplaced around the external iliac artery and externalized percutaneouslyas above as described in Duggan M J, et al. “Development of a lethal,closed-abdomen, arterial hemorrhage model in non-coagulopathic swine.”J. Surg. Res. 2014; 187: 536-541 (“Duggan 2”), which is herebyincorporated by reference in its entirety and for all purposes. Also asabove, following closure of a midline incision, the wire was pulled,resulting again in a severe, uncontrolled, closed cavity injury, andmassive hypotension which was over 80% lethal at one hour in the absenceof intervention.

These models were selected to approximate certain conditions in whichthe systems and methods of the current invention are used, namelyintra-cavity and/or noncompressible hemorrhages, or hemorrhages whichresult in sudden and severe hypotension and/or which are lethal in theabsence of an intervention.

In both models, the hemorrhage was generated in, and foams were deployedinto, the abdominal cavity. The pressure within the abdomen (the“intra-abdominal pressure” or “IAP”) was measured in all animals bycontinually monitoring bladder pressure through an intraabdominalpressure device (Abviser), consistent with clinical practice inmeasurement of IAP.

In Situ Forming Foams

According to various embodiments of the invention, a patient sufferingfrom a closed-cavity or non-compressible hemorrhage is treated byadministering an in situ forming foam as described in Zugates I and IIand Sharma I and II. In preferred embodiments, the liquid phases include(a) an isocyanate to generate gas and crosslink and (b) a polyol tocontrol the foam properties upon reaction with the isocyanate. Theformulation reacts to generate a foam within two minutes of itsdeployment into the body, and is characterized by the parameters shownin Table 1, below.

TABLE 1 PHYSICAL CHARACTERISTICS OF FOAMS USED VOLUME EXPANSION:26.2-85.3 fold COMPRESSION FORCE  2.2-10.1 kPa DEFLECTION (CFD) AT 50%DEFLECTION: WATER UPTAKE:  2.7-7.7 g/g RISE TIME: 47.4-80.4 s

In preferred embodiments, administration of foams of the invention causea rapid, transient increase or spike in pressure within the cavity orwithin a portion of a boundary of a cavity containing a hemorrhage.Following the spike the pressure preferably remains elevated at asteady-state value or within a steady-state range that is less than thepeak pressure for an extended period of time. Exemplary temporalpressure profiles which include spikes and steady-state pressure rangesare shown for various doses of foam in FIG. 1. The steady-state pressuremay persist for a suitable interval which permits evacuation of thepatient to a site where medical treatment is available, for instanceabout 60, 90, 120, 150, 180, 210 or 240 minutes, or longer. Themagnitude of the pressure spike may vary depending on the formulationand dose used, so that different device formulations and/or doses mightbe selected to suit different applications and different patient bodysizes or types. Additionally, the magnitude of the steady state pressuremay be dose dependent, and may be affected by interventions which affectthe rate of foaming, cross-linking, or degradation of the foam. Forinstance, in some embodiments, a user may decrease a steady-statepressure by applying a material which tends to degrade the foam in aquantity selected to rapidly degrade a portion of the foam. In otherembodiments, the delivery system may modulate peak or steady statepressure through a dose modulation feature, a relief valve, or a similarfeature. Exemplary materials are described in Sharma I and in Zugates Iand II. Delivery systems and methods suitable for use in connection withmethods of the present invention are set forth in Sharma II.

The pressure spike ensures that sufficient force is applied to theboundaries of the body cavity and/or the injury site to effectivelyclose hemorrhaging. Studies by others have generally shown thatsustained, elevated pressure within body cavities, and particularlyelevated IAP above 20 mmHg can have adverse effects on patients. Forexample, Vivier et al. (“Effects of increased intra-abdominal pressureon central circulation”, Br. J. Anaesthesia 96(6): 701-7 (2006), whichis hereby incorporated by reference for all purposes), found vascularchanges including increases in left ventricular end-diastolic area andpressure (markers of increased cardiac preload) were significantlyincreased at elevated IAP values.

Sustained IAP values of 20 mmHg and concomitant organ system failure areclassified as “compartment syndrome,” a condition characterized by pain,paralysis, paresthesia, and other undesirable effects including, in someinstances, lethality. In compartment syndrome, increased compartmentalpressure limits blood supply to muscles and nerves within thecompartment. In an effort to avoid undesirable changes in circulationand/or compartment syndrome, prior art systems and methods have beendesigned to limit applied compartmental pressures to values below about20 mmHg or about 30 mmHg.

In spite of the risks associated with sustained, elevated IAP, somestudies have suggested that elevated IAP may be useful in reducinghemorrhage in some animal models. For example, Sava, et al., “Abdominalinsufflation for prevention of exsanguination,” J. Trauma 2003, March;54(3): 590-4 found that, in a swine model in which a 2.7 mm hole wasmade in the inferior vena cava in which animals were euthanized after 15minutes of monitoring, CO₂ insufflation resulted in significantly lowerblood loss and significantly higher arterial pressure relative tocontrol. Velmahos, et al. “Abdominal insufflation decreases blood losswithout worsening the inflammatory response: implications forprehospital control of internal bleeding” found that, in a swine modelinvolving a lacerated spleen, CO₂ insufflation reduced blood lossrelative to control. Finally, Jaskille, et al. “Abdominal insufflationdecreases blood loss and mortality after porcine liver injury.” J.Trauma 2005 December; 59(6)1305-8; discussion 1308, found that CO₂insufflation at 20 cmH₂O in a swine model of blunt liver trauma reducedblood loss by 69%. (Each of the foregoing references is herebyincorporated by reference for all purposes.) However, these studies havenot found elevated IAP to be completely effective in reducing hemorrhageor improving survival of lethal abdominal hemorrhages, and they have notdemonstrated extended survival without significant adverse effects.

The inventors have found that pressure profiles such as those shown inFIG. 1 are effective in treating life-threatening non-compressiblehemorrhage in swine (as discussed in greater detail below), whileavoiding complications associated with compartment syndrome. Withoutwishing to be bound to any theory, it is believed that a transientapplication of high-pressure within a cavity rapidly prevents ongoinghemorrhage from injured vasculature and permits clots formation in theabsence of robust ongoing flow. The application of a lower, but stillelevated steady-state pressure maintains hemostasis.

The inventors have also found that, while pressure alone is sufficientto achieve some reduction in hemorrhage, and to improve survivabilityfrom non-compressible hemorrhage, the application of pressure by a foamsuch as an in situ forming foam or another material having a solid orpartially solid surface improves the efficacy of the systems and methodsof the invention. While pressures may be applied by a variety of means,including gas or liquid insufflation, the use of foams to treathemorrhages in cavities may be particularly advantageous. Though notwishing to be bound to any theory, it is believed that threecharacteristics of the foams described above and in Sharma I and ZugatesI and II are particularly useful in treating hemorrhages: first, the insitu reaction of the foam device spontaneously creates a transientincrease in pressure, followed by a return to steady state. The foamsystem does not require monitoring or feedback systems. Second, the foamsystem is portable and easily administered. Third, the material providesa solid, steady source of intraabdominal pressure. It does not readilyleak, nor is it generally absorbed by the body. Therefore, the pressuredoes not need to be maintained by the addition of materials.

In spite of the advantages of in situ forming foams for treatment ofhemorrhages in cavities, other treatment systems and methods are withinthe scope of the invention insofar as it is possible to achieve thepressure profiles discussed above using these systems and methods. Asnon-limiting examples, gels, elastomeric solids, pre-formed foams, orcombinations of foams and liquids or foams and gasses can be utilized toapply pressure to the cavity or a portion of the boundary of the cavity(including injured tissue and tissues adjacent to injured tissue).Additionally, materials which undergo phase changes within cavities, forexample reverse thermosensitive materials including poloxamers, andelectromechanical or hydraulic devices can be used to deliver pressureto hemorrhages within cavities. And pressure may be delivered viamaterials, systems and devices deployed either within the cavity oroutside of the cavity (e.g. adjacent to the cavity). In someembodiments, the cavity is constricted from the outside, for example byconstricting the abdomen from the exterior.

Pressure can be generated in certain models through the delivery and/orremoval of material (e.g. liquid, gas, gel, foam) to apply pressure tothe cavity, and the pressure applied may be controlled manually by anend user, mechanically by a governing device such as a valve (e.g. acheck valve), or by computerized means.

The principles of the invention in its various embodiments are furtherillustrated by the following non-limiting examples:

EXAMPLE 1 Dose-Dependent Changes in Spike and Steady-State PressureValues and Survival in a Hepatic Hemorrhage Model

In situ forming foams were delivered in the grade V hepatic-portal modeldescribed above. Animals were given 64 ml, 85 ml, 100 ml or 120 ml ofliquid-phase in situ forming foam formulations, or sham treatment in thecase of control animals, and IAP was measured over an interval of 3hours. As shown in FIG. 1, control animals showed only a minor increasein IAP over the first 20 minutes of the experiment, while foam-treatedanimals displayed dose-dependent changes in spike pressures andsteady-state pressures. In addition, survival was quantitated foranimals in each treatment category.

Foam dosages in the swine models used herein are likely to be largerthan the volumes used in humans, owing to differences in the volume ofthe abdominal cavity.

The control group was lethal in 11 of 12 animals (8.3% survival), with amedian survival time of 23 minutes (quartile 20-38). Survival rate withhepato-portal injury was highest at the 120 ml dose (90%; p=0.0002) anddecreased in a dose-dependent fashion: 100 ml (72.2%; p=0.0007), 85 ml(33.3%; p=0.22), and 64 ml (16.7%; p=0.47). The Kaplan-Meier graph ofall groups is shown in FIG. 2. Median survival time was 180 (180-180)minutes at 120 mL, 180 (161-180) minutes at 100 mL, 89 (81-158) minutesat 85 mL, and 55 (40-68) at 64 mL. Relative to controls, survival timeas measured by the log-rank test was significantly improved in allgroups. Hemorrhage rate was also reduced in all groups, but lowest inthe 120 mL dose group vs. control group (0.34±0.052 vs. 3.0±1.3ml/kg/min, p=0.001).

A relationship was also identified between peak (spike) pressure andsurvival time in swine. FIG. 3 plots survival time against peak pressurevalues observed in 69 pooled experiments. A significant survival benefitwas observed for higher peak pressures as described in the Table 2:

TABLE 2 MEAN SURVIVAL TIME AS A FUNCTION OF PEAK IAP. Peak IAP (mmHg)Mean survival time (mm) <20 46 20 to 69 141 >69 170

A relationship was also identified between steady-state pressure andsurvival time in swine. FIG. 4 plots the IAP measured 30 minutes afterinjury against survival time, and indicates that survival improved atsteady-state pressures at or above 18 mmHg, and improved further atsteady state pressures at or above 28 mmHg (see Table 3):

TABLE 3 MEAN SURVIVAL TIME AS A FUNCTION OF IAP AT 30 MINUTESPOST-INJURY. IAP at 30 minutes post- Mean survival injury (mmHg) time(min) >28 55 14 to 28 149 >28 165

EXAMPLE 2 Dose-Dependent Changes in Spike and Steady-State PressureValues and Survival in an Arterial Hemorrhage Model

Similar experiments were conducted in the arterial hemorrhage modeldescribed above. As shown in FIGS. 5 and 6, dose dependent effects onTAP and survival were observed in this model as well. There was anoticeable increase in percent survival at 1 hour for the 120 ml and 100ml test groups relative to the control group (84% and 82%, respectively,vs. 14%; p<0.001). Hemorrhage rate at the experimental endpoint wassignificantly lower in both foam groups relative to the control.

By way of summary of the foregoing examples, Table 4 below depicts sixexemplary experiments in which varying quantities of an in situ foamingformulation was administered to porcine in a liver hemorrhage and aniliac hemorrhage model.

TABLE 4 TRANSIENT PEAK AND STEADY STATE PRESSURES OBSERVED IN VARIOUSEXPERIMENTS. Liver Hemorrhage Model Iliac Artery Hemorrhage Model SwinePeak Steady State Peak Steady State Foam Pressure Pressure PressurePressure Dose (mmHg) (mmHg) (mmHg) (mmHg) 120 mL 86 28 44 16 100 mL 5125 22 12  85 mL 21 18 — —  64 mL 14 14 — —

All doses tested here demonstrated safety and a survival benefit. As thetable illustrates, the peak pressures observed range from 14 to 86 mmHgin the liver hemorrhage model and from 22 to 44 mmHg in the iliac arteryacross both hemorrhage models. Steady state values ranged from 12 to 20mmHg in both injury models.

EXAMPLE 3 Approximation of Survival Effects by Gas Insufflation withFoam-Like Pressure Kinetics

While not wishing to be bound to any theory, it is believed that thefoams disclosed above and used in the previous examples generatedpressure spikes by one or more of a rapid increase in the volume of thefoam, gas generated from the blowing reaction, gas generated and notfully contained by the foam, etc. The reduction in pressure to thesteady state values, in turn, may have been due to one or more of aviscoelastic response of the tissues in the abdominal cavity, a changein fundamental abdominal volume, possibly caused by the relaxation oftissues in the abdomen, a reduction in the volume of the foam, gastransfer, etc.

In the models examined, larger doses of foam were associated with largerpeak pressures, as shown in FIG. 1, and with improved survival, as shownin FIG. 2. To examine the relationship between the survival effect andthe TAP profiles achieved, controls and animals treated with 100 ml offoam formulation were compared with animals treated by a CO2 gasinsufflation protocol which approximated the pressure profile observedin foam treated animals. The various IAP measurements from the threegroups are presented in FIG. 7. In gas treated animals, 1-hour survivalwas about 75%, while three hour survival was about 50%. Although thesevalues did not match those seen in the highest-dose cohorts offoam-treated animals, they did suggest that employing gas insufflationor another pressure-generating technique to achieve a pressure profilethat includes a transient spike or peak followed by a steady statepressure is a potentially effective treatment for hemorrhage.

EXAMPLE 4 Observation of Spike-and-Steady State Pressure Profiles inRecently Deceased Human Subjects

To understand performance in representative human anatomy, the ArsenalFoam System was deployed in recently deceased human subjects. Subjectswith no abdominal pathology or prior surgery were identified andinformed consent was obtained from family members post-mortem. Withinthree hours of death, the abdomen was accessed and 1500 mL fluid wasadded to simulate severe hemorrhage. Self-expanding polyurethane foamwas administered at multiple doses using a prototype delivery system.Intraabdominal pressure was monitored as a function of time for 15minutes, after which the foam was removed and contact with abdominaltissues was evaluated.

The Arsenal Foam System was successfully deployment in 10 subjectswithin three hours post-mortem. Intraabdominal pressure was recorded, asshown for a representative sample in FIG. 8.

Foam administration resulted in a rapid, transient, and dose-dependentpeak in intraabominal pressure following deployment in humans. Notably,the shape of the curves was similar to that observed in animal models,suggesting that the foam system results in a characteristicintraabdominal pressure following deployment.

Because subjects in this study were not alive, safety and efficacy ofthe foam at varying doses could not be measured directly. However,pressure can be used as a surrogate endpoint to link results in swine toresults in recently deceased humans. These results suggest that theintraabdominal pressure profiles observed in swine can be matched inhumans. While not wishing to be bound by any theory, it is believed thathuman doses which result in the intraabdominal pressure profilesobserved to be effective in swine models will be safe and effective inhumans.

EXAMPLE 5 Dose-Ranging Foam Performance in Recently Deceased HumanSubjects

The study described in Example 4 was conducted across a range of foamdoses with initial volumes. Terminal patients were identified, and thestudy was conducted within three hours of death. The abdomen wasaccessed and 1500 mL fluid was added to simulate abdominal hemorrhage.Self-expanding foam was delivered at multiple doses (initial volumes of45, 55, 65, 75, and 100 mL). Intra-abdominal pressure was monitored for15 minutes, then foam was removed via laparotomy to assess abdominaltissue contact.

N=21 recently deceased patients ranging in age from 20 to 92 years andBMI 18 to 39 kg/m² were enrolled in the study. Administration of foam atdoses ranging from 45 to 100 mL resulted in final foam volumes rangingbetween 911 and 3165 mL. This corresponds to foam volume expansionranging between 21-fold and 43-fold the initial volume. Materialproperties of the foam in these studies are reported in Table 5:

TABLE 5 MATERIAL PROPERTIES OF SELF-EXPANDING FOAM IN RECENTLY DECEASEDHUMAN SUBJECTS Parameter Observed Range Expansion 21x-43x Final Volume911-3165 mL Compression Force Deflection  4.9-9.2 kPa Water Uptake 3.7-9.5 g/g

Foam administration resulted in a characteristic intra-abdominalpressure curve wherein pressure increased rapidly to reach a peakpressure, then dissipated toward baseline levels. The intra-abdominalpressure profile was similar in recently deceased human subjects and inswine, as indicated in FIG. 9.

As seen from FIG. 10, 45 mL, 55 mL, and 65 mL doses in recently deceasedhuman subjects resulted in peak pressures of 37±20, 28±8.1, and 33±20mmHg, respectively, within the acceptable range established in swinestudies, shown as horizontal lines in FIG. 10. On the other hand, 75 mLand 100 mL foam deployments exceeded acceptable pressures defined inswine.

In this study intra-abdominal pressure in recently deceased humansubjects increased to peak levels between 13 and 125 mmHg (absolutelevels). Adjusting for variations in subject baseline pressure, peakabdominal pressure varied between 6 and 112 mmHg (FIG. 10).

Foam treatment resulted in distension of the abdominal cavity inrecently deceased human subjects. In this regard, the circumference atthe umbilicus was measured and was found to increase between 0.6 and 9.5cm within two minutes of foam deployment as shown in FIG. 11. Distensionwas not observed to be dose dependent.

Foam conformed to human anatomy and contacted organs throughout theabdomen. Organ contact was dose dependent as illustrated in thegraphical representation of abdominal organ contact shown in FIG. 12.Foam was found to contact the following organs: bladder, small bowel,large bowel, omentum, liver, spleen, paracolic gutters, and thediaphragm. More widespread distribution throughout the abdomen wasgenerally observed with increasing initial foam doses. Swine data areshown in A; recently deceased study data are shown in B-F. Contact withthe omentum is not depicted, as the omentum frequently overlapped thesmall bowel and prevented organ contact.

Foam was removed from the abdomen. Representative images of foamappearance during and after removal are shown in FIGS. 13A-D. Afterremoval from the abdomen, foam was measured along the midline todetermine the distance between the cranial and pelvic edges of the foam,the left and right edges, and the depth measured from the bottom of thefoam to the top of the foam. The dimensions of foams administered inthis study are shown in Table 6:

TABLE 6 MATERIAL PROPERTIES OF SELF-EXPANDING FOAM IN RECENTLY DECEASEDHUMAN SUBJECTS. Dimension Observed Range Cranial-Caudal Distance  19-40cm Left-Right Distance  18-36 cm Depth 6.5-15 cm

Without being bound to theory, it is believed that human doses whichresult in the intra-abdominal pressure profiles observed to be effectiveand safe in swine models will be safe and effective in humans.

CONCLUSION

The phrase “and/or,” as used herein should be understood to mean “eitheror both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in othercases. Other elements may optionally be present other than the elementsspecifically identified by the “and/or” clause, whether related orunrelated to those elements specifically identified unless clearlyindicated to the contrary. Thus, as a nonlimiting example, a referenceto “A and/or B,” when used in conjunction with open-ended language suchas “comprising” can refer, in one embodiment, to A without B (optionallyincluding elements other than B); in another embodiment, to B without A(optionally including elements other than A); in yet another embodiment,to both A and B (optionally including other elements); etc.

The term “cavity’ as used herein means closed body compartments such asthe abdominal cavity, the thoracic cavity, etc., as well as cavitiesthat are open, such as junctional wounds, and “pseudocavities” in whichat least one boundary of the cavity is defined by a structure other thanan organ or a tissue, (e.g. a bandage).

The term “consists essentially of” means excluding other materials thatcontribute to function, unless otherwise defined herein. Nonetheless,such other materials may be present, collectively or individually, intrace amounts.

As used in this specification, the term “substantially,” “approximately”or “about” means plus or minus 10% (e.g., by weight or by volume), andin some embodiments, plus or minus 5%. Reference throughout thisspecification to “one example,” “an example,” “one embodiment,” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the example is included inat least one example of the present technology. Thus, the occurrences ofthe phrases “in one example,” “in an example,” “one embodiment,” or “anembodiment” in various places throughout this specification are notnecessarily all referring to the same example. Furthermore, theparticular features, structures, routines, steps, or characteristics maybe combined in any suitable manner in one or more examples of thetechnology. The headings provided herein are for convenience only andare not intended to limit or interpret the scope or meaning of theclaimed technology.

Certain embodiments of the present invention have described above. Itis, however, expressly noted that the present invention is not limitedto those embodiments, but rather the intention is that additions andmodifications to what was expressly described herein are also includedwithin the scope of the invention. Moreover, it is to be understood thatthe features of the various embodiments described herein were notmutually exclusive and can exist in various combinations andpermutations, even if such combinations or permutations were not madeexpress herein, without departing from the spirit and scope of theinvention. In fact, variations, modifications, and other implementationsof what was described herein will occur to those of ordinary skill inthe art without departing from the spirit and the scope of theinvention. As such, the invention is not to be defined only by thepreceding illustrative description.

The invention claimed is:
 1. A kit for treating hemorrhage in a cavityof a patient, the kit comprising: a formulation comprising at least oneliquid phase, the formulation configured to form a foam when disposedinto the cavity, wherein the foam exerts a pressure on an interiorboundary of the cavity, said pressure characterized by a transient peakvalue; and instructions instructing a user in the application of theformulation.
 2. The kit of claim 1, wherein the transient peak value isless than about 84 mmHg.
 3. The kit of claim 1, wherein the transientpeak value is at least about 51 mmHg.
 4. The kit of claim 1, wherein thetransient peak value is at least about 20 mmHg.
 5. The kit of claim 1,wherein the pressure characterized by a transient peak value and atleast one steady state value.
 6. The kit of claim 1, wherein the cavityis a human abdominal cavity.
 7. The kit of claim 1, wherein theformulation is provided in a dosage ranging from 45 mL to 100 mL.
 8. Thekit of claim 1, wherein the formulation is provided in a dosage rangingfrom 45 mL to <75 mL.
 9. The kit of claim 1, wherein the formulation isprovided in a dosage ranging from 45 mL to 65 mL.
 10. The kit of claim1, wherein a volume of the foam that is formed ranges from 900 mL to3200 mL.